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The B55α-containing PP2A holoenzyme dephosphorylates FOXO1 in islet β-cells under oxidative stress

Ling Yan1, Shuangli Guo, Marie Brault

  • 1Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

The Biochemical Journal
|March 16, 2012
PubMed

Insights

Protein phosphatase 2A (PP2A) with the B55α subunit regulates forkhead box O1 (FOXO1) nuclear import in pancreatic beta cells. This mechanism is crucial for managing oxidative stress and cellular dysfunction in Type 2 diabetes.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Endocrinology

Background:

  • The transcription factor FOXO1 (forkhead box O1) plays a critical role in cellular processes like metabolism, proliferation, and cell death.
  • FOXO1's subcellular localization, and thus its transcriptional activity, is regulated by reversible phosphorylation.
  • Oxidative stress in pancreatic islet beta-cells is linked to cellular dysfunction in Type 2 diabetes.

Purpose of the Study:

  • To investigate the mechanism of FOXO1 dephosphorylation and nuclear translocation in pancreatic islet beta-cells under oxidative stress.
  • To identify the specific protein phosphatase 2A (PP2A) holoenzyme involved in regulating FOXO1 nuclear import.
  • To determine the role of this PP2A holoenzyme in cellular response to oxidative stress and its relevance to Type 2 diabetes.

Main Methods:

  • Biochemical and molecular approaches were used to isolate and characterize the PP2A holoenzyme associated with FOXO1.
  • Chemical cross-linking and mass spectrometry (MS) were employed to identify protein-protein interactions.
  • Gene knockdown of the B55α regulatory subunit was performed in INS-1 cells to assess its functional impact on FOXO1 localization and cell survival.

Main Results:

  • A PP2A holoenzyme containing catalytic (C), structural (A), and B55α regulatory subunits was found to associate with FOXO1.
  • Knockdown of B55α inhibited FOXO1 dephosphorylation and nuclear translocation, and attenuated oxidative stress-induced cell death in INS-1 cells.
  • Increased levels of B55α and nuclear FOXO1 were observed in islets from db/db mice, an animal model of Type 2 diabetes, under hyperglycaemic conditions.

Conclusions:

  • The B55α-containing PP2A holoenzyme is a key regulator of FOXO1 activity, specifically mediating its nuclear import.
  • This PP2A-FOXO1 pathway is important for pancreatic beta-cell function under oxidative stress.
  • The findings highlight a potential therapeutic target for managing Type 2 diabetes-associated cellular dysfunction.

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